Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000179.2 | RefSeq Select | 4435 nt | 153–4235 |
| NM_000179.1 | Alternative | 4264 nt | 88–4170 |
| NM_000179.3 | MANE Select | 4265 nt | 90–4172 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThe MSH6 c.-2G>T variant has been reported in the published literature in an individual with colorectal cancer (PMID: 34197922 (2021)) and in an individual with a family history of pancreatic cancer (PMID: 33939675 (2021)). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
Variant summary: MSH6 c.-2G>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 1.2e-05 in 244064 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-2G>T has been reported in the literature (Liu_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26888055). ClinVar contains an entry for this variant (Variation ID: 142219). Based on the evidence outlined above, the variant was classified as uncertain significance.
"This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Likely benign (5 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 135 bp |
| Donor Loss (DL) | 0.41 | -1 bp |
| Acceptor Gain (AG) | 0.0 | -70 bp |
| Donor Gain (DG) | 0.02 | 238 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: 'Very Strong Strength: Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) a ≤ codon 1341 in MSH6.' The evidence for this variant shows: it is a noncoding 5′ UTR variant (c.-2G>T) not predicted to introduce a premature stop codon. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: 'Strong Strength: A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic.' The evidence for this variant shows: it is not a missense variant and does not alter an amino acid. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: 'Very Strong Strength: Very Strong ≥ 4 de novo points.' The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: 'Strong Strength: Strong Calibrated functional assays with functional odds for Pathogenicity > 18.7.' The evidence for this variant shows: no functional assay data exist for c.-2G>T. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.' The evidence for this variant shows: no case-control or patient cohort data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot and/or critical and well-established functional domain without benign variation.' The evidence for this variant shows: c.-2G>T lies in the 5′ UTR, not in a known functional domain. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: 'Supporting Strength: Supporting Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset.' The evidence for this variant shows: observed at 4/275,398 alleles (MAF=0.00145%, ~1 in 68,850) which is below 1 in 50,000. Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant.' The evidence for this variant shows: no data on trans observations. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants not in repetitive regions.' The evidence for this variant shows: c.-2G>T does not alter protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different missense change was classified as Pathogenic.' The evidence for this variant shows: it is not a missense variant. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity/maternity.' The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'Cosegregation with disease in multiple affected family members.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.' The evidence for this variant shows: c.-2G>T is noncoding. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect.' The evidence for this variant shows: in silico prediction (CADD=1.04) is benign and SpliceAI score=0.41 is below high-confidence threshold for splicing; overall computational evidence is inconclusive. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no phenotype/tumor data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source recently reports variant as pathogenic but the evidence is not available to the laboratory to perform an independent evaluation.' The evidence for this variant shows: ClinVar submissions are VUS or Likely benign. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone Strength: GnomAD v4 Grpmax filtering allele frequency ≥ 0.0022.' The evidence for this variant shows: MAF=0.0000145 < 0.0022. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'Strong Strength: GnomAD v4 Grpmax filtering allele frequency ≥ 0.00022 and < 0.0022.' The evidence for this variant shows: MAF=0.0000145 < 0.00022. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: 'Strong Strength: Co-occurrence in trans with a known pathogenic variant in the same gene in a patient without CMMRD.' The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: 'Strong Strength: Calibrated functional assays with functional odds for Pathogenicity ≤ 0.05.' The evidence for this variant shows: no functional assay data. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: 'Strong Strength: Lack of co-segregation with disease in pedigree(s) with a combined Bayes LR h < 0.05.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene for which primarily truncating variants are known to cause disease.' The evidence for this variant shows: it is noncoding. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant in a patient with a recessive disorder or in cis with another pathogenic variant.' The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in repetitive regions without known function.' The evidence for this variant shows: it is a single-nucleotide change in the UTR. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product.' The evidence for this variant shows: conflicting in silico results (CADD benign, SpliceAI possible but below high-confidence threshold). Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no such case data. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source recently reports variant as benign but the evidence is not available to the laboratory to perform an independent evaluation.' The evidence for this variant shows: ClinVar entries are conflicting (VUS/Likely benign) and not solely benign. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'A synonymous variant for which splicing prediction algorithms predict no impact on splicing.' The evidence for this variant shows: it is not synonymous but UTR. Therefore, this criterion is not applied.